Bone Center

The Bone Marrow Microenvironment in Multiple Myeloma

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Multiple myeloma is the second most common adult hematological malignancy
One of the major clinical features is the development of a destructive osteolytic bone disease, characterized by osteolytic bone lesions, osteoporosis, hypercalcaemia, pathological fractures and severe bone pain
Myeloma bone disease is associated with an increase in osteoclastic bone resorption and a decrease in osteoblastic bone formation
Despite recent therapeutic advances, myeloma remains an incurable malignancy with median survival rates of only 3 years.

The Vicious Cycle

Myeloma cells are located in the bone marrow microenvironment, close to sites of active bone resorption, where they are ideally placed to interact with a range of cell types, including osteoclasts and osteoblasts. These interactions promote both the development of myeloma bone disease and tumor growth and survival
Our research is focused upon identifying the complex molecular mechanisms which mediate the development of myeloma bone disease and tumor growth and survival within the bone microenvironment

Personnel:

Gregory Mundy; Director of Bone Center
Claire Edwards; Research assistant professor
Andrew Hart; Clinical research fellow
Junling Zhuang; Postdoctoral research fellow
Jessica Fowler; Graduate student
Andreia Bates; Graduate student
Seint Lwin; Research assistant II

Current Projects:

These projects all use a combination of in vitro cellular and molecular approaches, and an in vivo murine model of myeloma. Using a murine model of myeloma enables us to fully study myeloma bone disease, tumor burden both within bone and at non-bone sites. The model can use a murine myeloma cell line, allowing genetic manipulation of the myeloma cells to study molecular mechanisms within the tumor cells in vivo. The host microenvironment can be studied using both pharmacological approaches and genetic mouse models.

•Techniques to study myeloma tumor burden in vivo include imaging (GFP, bioluminescence), flow cytometry, bone histomorphometry and ELISA.

•Techniques to study myeloma bone disease in vivo include imaging (microCT, X-ray), bone histomorphometry and biomechanics.

•In vitro techniques commonly used include; cell culture (myeloma, osteoblast, osteoclast), real-time PCR, western blotting, ELISA, flow cytometry, transfection, luciferase assays, microscopy, immunohistochemistry.

Current projects investigate several different aspects of multiple myeloma and the associated bone disease, including;

(i)The effect of targeting both tumor cells and the host microenvironment using proteasome inhibitors (Claire Edwards)

(ii)The role of cells of the host bone marrow microenvironment in myeloma initiation and progression (Jessica Fowler, Claire Edwards)

(iii)The role of host-derived MMPs in myeloma bone disease (Claire Edwards in collaboration with Conor Lynch)

(iv)The role of specific myeloid immune suppressor cells in myeloma bone disease (Junling Zhuang)

(v)The anti-tumor effect of bisphosphonates in myeloma (Junling Zhuang)

(vi)Targeting the TGF-b signaling pathway in myeloma bone disease (Andrew Hart)

(vii)The role of novel receptors and ligands in myeloma bone disease (Andreia Bates, Claire Edwards)

Publications

•Edwards, C.M., Edwards, J.R., Esparza, J., Oyajobi, B.O., McCluskey, B., Munoz, S., Grubbs, B., Mundy, G.R. (2007) Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo. Blood. 111; 2833-2842.

•Edwards, C.M., Zhuang, J., Mundy, G.R. The pathogenesis of the bone disease of multiple myeloma. Bone (in press).

•Edwards, C.M. Wnt signaling; Bone’s defense against myeloma. Blood (in press).

Abstracts (* indicates oral presentation)

•*Edwards, C.M., Lynch, C.L., Fower, J.A., Carter, K., Lwin, S.T., Matrisian, L.M., Mundy, G.R. Differential effects of host-derived MMPs on development of multiple myeloma in vivo. IBMS Davos Workshops: Bone Biology & Therapeutics, Davos, Switzerland (2008). Bone, 42(1): 196

•*Edwards, C.M., Edwards, J.R., Lwin, S.T., Mundy, G.R. Targeting Wnt signaling in myeloma in vivo; differential effects on tumor burden and myeloma bone disease. 49th Annual Meeting of the American Society of Hematology, Atlanta, USA (2007). Blood, 110(11): 249a

•*Edwards, C.M., Caldwell, R.L., Bates, A.L., Fowler, J.A., Edwards, J.R., Lwin, S.T., Zhang, J., Mundy, G.R. Protein profiling in myeloma in vivo; effects of Velcade in a mouse model of myeloma. 49th Annual Meeting of the American Society of Hematology, Atlanta, USA (2007). Blood, 110(11): 82a

•*Bates, AL., Parker, R., Mundy, G.R., Edwards, C.M. Myeloma Cells Decrease EphB4 Expression in Osteoblasts; A Novel Mechanism for Regulation of Bone Formation in Multiple Myeloma. 29th Annual Meeting of the American Society for Bone and Mineral Research, Honolulu, USA (2007). J Bone Miner Res, 22 (Suppl 1):S86

•*Zhuang, J., Yang, L., Edwards, J.R., Edwards, C.M., Mundy, G.R. Osteoclasts in myeloma are derived from Gr-1+CDllb+ mononuclear cells of the bone marrow niche. 29th Annual Meeting of the American Society for Bone and Mineral Research, Honolulu, USA (2007). J Bone Miner Res, 22 (Suppl 1):S2

•Edwards, C.M., Fowler, J.A., Caldwell, R.L., Bates, A.L., Edwards, J.R., Zhang, J., Foehr, D.E., Parker, R., Roberts, A., Mundy, G.R. The ubiquitin-proteasome pathway is dysregulated in myeloma cells in the bone microenvironment in vivo. 29th Annual Meeting of the American Society for Bone and Mineral Research, Honolulu, USA (2007). J Bone Miner Res, 22 (Suppl 1):S190

Edwards, C.M., Edwards, J.R., Esparza, J., Oyajobi, B.O., McCluskey, B., Munoz, S.A., Grubbs, B., Mundy, G.R. Lithium inhibits the development of myeloma bone disease in vivo. 28th Annual Meeting of the American Society for Bone and Mineral Research, Philadelphia, USA. (2006) J Bone Miner Res, 21(suppl.1) S82

The VUMC Center for Bone Biology is a member of the VUMC Department of Medicine in the Division of Clinical Pharmacology.

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